Summary: Invertebrates express one endoplasmic reticulum (ER)-resident Ca ²⁺ -sensing stromal-interaction molecule (Stim) and one Orai plasma membrane channel protein. Stim conveys store depletion to Orai, mediating the evolutionarily conserved Ca ²⁺ release-activated Ca ²⁺ (CRAC) current. The crucial role of their vertebrate homologues, STIM1 and Orai1 in mediating CRAC activity in mammals is well-established. However, mammals possess two STIM and three Orai isoforms and the choreography of their interactions under physiological receptor activation is unknown. We show that the five mammalian STIM1/2 and Orai1/2/3 isoforms have non-redundant functions. Yet, all five isoforms are always required together to ensure the graded diversity of mammalian Ca ²⁺ signaling events in response to the full spectrum of agonist strengths. Receptor-activated Ca ²⁺ signaling across the range of stimulus intensities requires functional interactions between not only STIM1/2 and Orai1/2/3, but also IP ₃ R, ensuring that receptor-mediated Ca ²⁺ release is precisely tailored to Ca ²⁺ entry and activation of nuclear factor of activated T-cells (NFAT). This is orchestrated by two interdependent and counterbalancing paradigms: the N-termini Ca ²⁺ -binding ER-luminal domains of unactivated STIM1/2 inhibit IP ₃ R-evoked Ca ²⁺ release. Gradual increase in agonist intensity leads to gradual STIM1/2 activation and relief of IP ₃ R inhibition. Concomitantly, the cytosolic C-termini of activated STIM1/2 differentially interact with Orai1/2/3 proteins as agonist intensity increases. Thus, coordinated and omnitemporal functions of all five STIM/Orai proteins and IP ₃ Rs at the ER-lumen and cytosol translate the strength of agonist stimulation to precise levels of Ca ²⁺ release, Ca ²⁺ entry and NFAT induction, ensuring the diversity and fidelity of complex mammalian Ca ²⁺ signaling. Highlights: All five STIM/Orai and IP ₃ R are always required together in mammalian Ca ²⁺ signalling Unactivated STIM1/2 inhibit IP ₃ R and activated STIM1/2 cooperatively activate Orai1/2/3 STIM1 contribution increases and that of STIM2 decreases as agonist intensifies Graded IP ₃ R disinhibition and Orai activation tailor receptor activity to NFAT induction

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